Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that prior art forms part of the common general knowledge in Australia.
Microglial cells share many morphological and functional features with monocytes and microphages and are thought to contribute to inflammatory processes in the brain. Microglia are activated during brain ischaemia, infection, demyelination, neurodegeneration and tumorigenesis (Gonzalez-Scarano, F. and Baltuch, G. 1999. Annu Rev Neurosci, 22:219-240). On a cellular level, activation of microglial cells, like monocytic cells, results in the expression of pro-inflammatory mediators such as cyclo-oxygenase type 2 (COX-2), tumour necrosis factor-α (TNF-α) and nitric oxide (NO). NO is a free radical generated from -arginine by NO synthases (NOS) (Griffith, O. W. and Stuehr, D. J., 1995. Annu Rev Physiol., 5:707-736). It is involved in a wide range of physiological and pathological processes including the regulation of vascular homeostasis, neurotransmission and inflammation (Nathan, C. 1992. FASEB. J, 6:3051-3064). Three isoforms of NOS have been characterized. Neuronal (type I or nNOS and endothelial) (type III or eNOS) NOS are constitutively expressed and are mainly regulating posttranscriptionally by calmodulin-dependent pathways. The inducible NOS isoform (type II or iNOS) is not expressed in healthy tissues but is rapidly expressed de novo in many cell types including astrocytes and microglia in response to lipopolysaccharide (LPS), a bacterial wall component, or inflammatory cytokines such as interleukin-1β (IL-1β), TNF-α or IFN-γ (Galea, E., Feinstein, D. L., and Reis, D. J., 1992. Proc. Natl. Acad. Sci. USA., 89:10945-10949; Hu, S., Sheno, W. S., Peterson, P. K. and Chao, C. C., 1995. Glia., 15:491-494; Nathan, C. and Xie, Q. W., 1994. J. Biol. Chem., 269:13725-13728). When produced in excess amounts NO may promote neuronal death by reacting with superoxide anion to generate peroxynitrite (Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A. and Freeman, B. A., 1990. Prac. Natl. Acad. Sci. USA., 87:1620-1624). Consequently, overproduction of nitric oxide has been implicated in neurological disorders associated with neuronal damage including brain ischaemia, Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS) (Chabrier, P. E., Demerle-Pallardy, C. and Auguet, M. 1999, Cell. Molecule. Life Sci., 55:1029-1035).
Accordingly, in light of the severe and debilitating outcome associated with the development of neurological disorders, and the apparent increase in the instance of onset thereof, there is an urgent need to develop methods of therapeutically and/or prophylactically treating these disorders either in the form of adjunctive therapies to currently utilised treatments or as a replacement to some of the currently available medications and/or methods of treatment.
In work leading up to the present invention, the inventors have determined that compounds of formula (I):
wherein each of R1 and R2 is independently selected from a hydrogen atom or a C1-C4alkyl group, R3 and R4 are each hydrogen atoms or together form another chemical bond, each X is independently selected from a hydroxyl group, a halogen atom, a C1-C4alkyl group or a C1-C4alkoxy group, or when two X groups are alkyl or alkoxy groups, they may be connected together to form a ring, and n is an integer from 1 to 3, downregulate iNOS expression and activity in microglial cells. Without limiting the present invention in any way, in light of the downstream production of nitric oxide which occurs subsequently to iNOS expression, these findings provide a means of downregulating nitric oxide over production and thereby a means of treating neurological disorders which are characterised by nitric oxide induced neuronal damage. The identification of this activity now permits the rational design of therapeutic and/or prophylactic regimes for modulating microglial cell functioning and, in particular, for downregulating endothelial cell iNOS expression.